AP865A - Heterecyclic compounds useful as inhibitors of cysteine protease. - Google Patents
Heterecyclic compounds useful as inhibitors of cysteine protease. Download PDFInfo
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- AP865A AP865A APAP/P/1997/001054A AP9701054A AP865A AP 865 A AP865 A AP 865A AP 9701054 A AP9701054 A AP 9701054A AP 865 A AP865 A AP 865A
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
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Abstract
Heterocyclic compounds useful as inhibitors of cysteine protease. A group of compounds of the formula (I) which are inhibitors of cysteine proteases particularly cathepsin K, and are useful in the treatment of excessive bone or cartilege loss.
Description
PROTEASE INHIBITORS
Field of the Invention
This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
Background of the Invention *
Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins Β, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin~G-therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature. The designation cathepsin K is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology).
Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone or i cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone I sialoprotein. Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing I zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption i lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget’s disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
It now has been discovered that a novel class of compounds are protease inhibitors, most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease.
Summary of the Invention
An object of the present invention is to provide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.
Accordingly, in the first aspect, this invention provides a compound according to formula (I).
In another aspect, this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
In yet another aspect, this invention provides a method of treating diseases in which the disease pa±ology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
Detailed Description of the Invention
The present invention provides compounds of formula (I):
wherein:
A is C(O) or CH(OH); R 1 is
, or R- is H, Cj.^alkyl, Cg-gcycloalkyl-CQ-galkyl, Ar-CQ_galkyl, Het-CQ.galkyl, R5C(O)-, R5C(S)-, r5sO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, adamantyl-C(O)-, or
R" is H, Cj^alkyl, Ar-Co-6alkyl, or Het-Co-galkyl; R'" is H, Cj.galkyl, C3.gcycloalkyl-CQ_6alkyl, Ar-Cg.^alkyl, or Het-CQ.galkyl; each R^ independently is H, C2_6alkenyl, C2-6alkynyl, Het, Ar or Cj-galkyl optionally substituted by OR', SR', NR'2, R’NC(O)OR5, CO2R', CO2NR'2, N(C=NH)NH2, Het or Ar; R^ is H, Ci-galkyl, C3_6cycloalkyl-CQ.galkyl, Ar-CQ_galkyl, Het-CQ.galkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, r5r'NC(O)-, R5R'NC(S)-, R'HNCH(R')C(O)-, or R50C(O)NR'CH(R')C(0)-; each R5 independently is C3_gcycloalkyl-Co_6alkyl, Ar-CQ_galkyl, Het-CQ_galkyl, Ar-CQ.galkoxy, Het-CQ.galkoxy, or Ci-fjalkyl optionally substituted by OR', SR', NR'2, R'NC(O)OR5, CO2R', CO2NR'2, N(C=NH)NH2, Het or Ar; R^ is H, C^.galkyl, Ar-Co-galkyl, or Het-Cg-galkyl and R? is H, Cj.galkyl, C3. 6cycloalkyl-C0.6alkyl, Ar-C0,6alkyl, Het-C0_6alkyl, R5C(O)~, R5C(S)-, R5SO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, R'HNCH(R')C(O)-, or R5OC(O)NR’CH(R')C(O)-; or R^ and R^ are connected to form a pyrrolidine, a piperidine, or a morpholine ring; each R' independently is H, Cj.galkyl, Ar-Co-6alkyl, or Het-Cg,galkyl; R* is H, Cj.galkyl, C3_6cycloalkyl-CQ_6alkyl, Ar-Cg.^alkyl, or Het-Co-galkyl; Y is a single bond or O;
each Z independently is CO or CHq: and n is 0 or 1 or a pharmaceutically acceptable salt thereof.
The present invention includes all hydrates, solvates, complexes and prodruss of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to formula (I) in vivc. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bends, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantlv in one form. *
The meaning of any substituent at any one occurrence in formula (I) or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
With respect to formula (I):
Preferably, A is C(O).
Suitably, RJ is
Particularly, in said R7 group, R' is H or CHg, PC is i-buty 1 and R“ is R-C(O)-, R^SOn-, R^OC(O)-, preferably. R-’ is Ar-CQ.galkvl or Het-CQ.galkyl. In particular, in said R^ group, R- is phenyl or benzyl which are unsubstituted or substituted by one or two of the group consisting of Cl, Br, F, CFg, C}.4alkyl, OH, Cj^alkoxy, CN, CONHp, NH2, or NO3, or substituted by methylenedioxy, or
Alternately, is
or
Suitably, is
. Suitably, in said R^ group, R^ is H or CH3, R^ is i-butyl and R^ is R^OC(O)- wherein R^ in said R^ group is Ar-Cg_galkyl or Het-CQ.galkyl. In particular, in said R^ group, R^ is phenyl or benzyl which are unsubstituted or substituted by one or two of the group consisting of Cl, Br, F, CF3, C^alkyl, OH, Ci_4alkoxy, CN, CONH2, NH2, or NO2, or substituted by methylenedioxy; or 2-, 3-, or 4-pyridyl-CH2-.
Alternately, R- is
in which X is CO, SO2, or CH2-CO and Y is a single bond or O.
Alternately, R~ is C3_6cycloalkyl-CQ.galkyl, Ar-Cq.galkyl, Het-Cq^alkyl, R^C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, R'HNCH(R')C(0)-, R5OC(O)NR'CH(R')C(O)-, or adamantyl-C(O)-.
Specific representative compounds of this invention are named in Examples 1-198 detailed and claimed hereinafter.
Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid «. abbreviations follow the IUBAC-IUB Joint Commission on Biochemical Nomenclature as U described in Eur. J. Biochem., 158, 9 (1984). The term "amino acid" as used herein refers c to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Γ "Ci-galkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, £ neopentyl and hexyl and the simple aliphatic isomers thereof. Any Cj-galkyl group may be £ optionally substituted independently by one or two halogens, SR', OR', N(R')2> C(0)N(R')2, carbamyl or Ci-4alkyl, where R' is H or Ci-6alkyl. Cqalkyl means that no alkyl group is present in the moiety. Thus, Ar-Cgalkyl is equivalent to Ar. "C3-6cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane. "C2-6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included. "C2-6alkynyI" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. "Halogen" or "halo" means F, Cl, Br, and I.
"Ar" or "aryl" means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-Cg.^alkyl, Het-CQ_galkyl, Cj.galkoxy, Ph-CQ_6alkoxy, Het-CQ_galkoxy, OH, (CH2)i-gNR R, O(CH2)i-6NR R; wherein each R independently is H, Cpgalkyl, Ar-CQ.galkyl, or Het-CQ.galkyl; or phenyl or naphthyl substituted by one to three moieties selected from Ci-4alkyl, OR', N(R')2, SR', CF3, NO2, CN, CO,R', CON(R'), F, Cl, Br and I, or substituted by a methylenedioxy group.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from Ci-4alkyl, OR', N(R')2, SR', CF3, NO2, CN, CO2R', CON(R'), F, Cl, Br and I, where R' is as defined hereinbefore. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, | oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, *
quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, _ J benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, | thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, benzothiazolyl, < benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6-napthyridinyl, 1,7-napthyridinyl, 1,8-napthyridinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl. "HetAr" or "heteroaryl" means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6- napthyridinyl, I, 7- napthyridinyl, 1,8- napthyridinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc or BOC refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz or CBZ refers to the benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide, DMAP is 2,6-dimethylaminopyridine, EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide. HOBT or HOBt refers to 1-hydroxybenzotriazole, DMF refers to dimethyl formamide, BOP refers to benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, DMAP is dimethylaminopyridine, DIEA refers to di-isopropylethylamine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, NMM is N-methylmorpholine, TFA refers to trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride, KHMDS refers to potassium hexamethyldisilazide, and THF refers to tetrahydrofuran. Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.
The compounds of formula (I) are generally prepared using a process which comprises: (A) for compounds in which A is CH(OH): (i) reacting a compound of the formula (M): (ΠΙ) or a salt thereof, wherein RJ, R", R"' and n are as defined in formula (I), with any reactive functional groups protected, with: (a) R^C(O)C1, in which R^is as defined in formula (I); or (b) R^C(O)OH, in which R^is as defined in formula (I), in the presence of EDC and HOBT; or (c) R^C(O)H, in which R^is as defined in formula (I), followed by reduction; or (d) R^OC(O)C1, in which R^is as defined in formula (I), in the presence of base; or (e) R^SO2C1, in which R^is as defined in formula (I), in the presence of base; or (f) wherein R^, r6 and R^ are as defined in formula (I); or
(g) adamantyl-C(O)Cl; (ii) reacting a compound of the formual (IV):
(IV) wherein R^, R'" and n are as defined in formula (I), with any reactive functional groups protected, with: * (a) , in which R-\ and R' are as defined in formula (I), in the presence of EDC and HOBT; or (b)
in which R* is as defined in formula (I), in the presence of EDC and HOBT; or (c)
, in which Y is as defined in formula (I), in the presence of EDC and HOBT; or (d)
(iii) reacting a compound of the formual (V):
(V) wherein R'" and n are as defined in formula (I), with any reactive functional groups protected, and Ra is Cj.galkyl, C3_6cycloalkyl-C0_6alkyl, Ar-Co^alkyl, or Het-C0.6alkyl with: (a) in which R^, R^ and R' are as defined in formula (I), in the presence of EDC and HOBT; or *
U r £ < (b) , in which R* is as defined in formula (I), Γ in the presence of EDC and HOBT; or c c < (c) , in which Y is as defined in formula (I), in the presence of EDC and HOBT; or (d)
(B) for compounds in which A is C(O): (i) reacting a compound of the formual (VI):
(VI) wherein R.1, R.2, R", R'" and n are as defined in formula (I), with any reactive functional groups protected, with ah oxidizing agent; and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
Compounds of the formula (I) are prepared by methods analogous to those described in Schemes 1-5.
Scheme 1
9
a) di-iert-butyl dicarbonate, CH2C12; b) m-chloroperoxybenzoic acid, CH2C12; c) NaN3, NH4CI, CH3OH:H2O (8:1); d) 10% Pd/C, CH3OH, H2; e) RCO2H, EDC, HOBt, CH2C12 ; f) HCl/EtOAc or TFA, CH2C12; g) RCO2H, EDC, HOBt, CH2C12 or RCOC1, TEA, CH2C12, TEA; h) CrO3, HOAc or DMSO, (COC1)2, CH2C12, TEA, -78°C to RT or DMSO, sulphur trioxide pyridine comple, TEA
Compounds of the general formula (I) wherein n is 0 or 1, and R- are amides
II and R is hydrogen are prepared as outlined in Scheme 1. Treatment of the commercially available 3-pyrroline (1-Scheme-1: n = 0 ) or 1,2,3,6-tetrahydropyridine (1-Scheme-1; n = i 1) under conditions which are known in the art for nitrogen protection, such as di-reri-butyl dicarbonate, gave 2-Scheme-1 (n = 0, 1). 2-Scheme-l is epoxidized by standard conditions, such as meta-chloroperoxybenzoic acid, to provide the epoxide 3-Scheme-l fn = 0,1). The epoxide 3-Scheme-l may be opened with sodium azide in a protic solvent, such as methanol and water, at an elevated temperature to give the azido alcohol 4-Scheme-l. The
1 azide 4-Scheme-l may be reduced to the amine 5-scheme-l by methods that are common to the art, such as hydrogen with palladium on carbon as a catalyst, in a protic solvent, such as methanol or ethanol. The amine 5-Scheme-l is acylated under standard conditions with EDC, HOBt and a carboxylic acid in an aprotic solvent, such as dichloromethane or DMF, to give 6-scheme-l. The amine 5-Scheme-l may also be acylated with an acid chloride in the presence of an organic base such as triethylamine or N-methyl morpholine in an I aprotic solvent such as dichloromethane to give the amide derivative 6-Scheme-l. The ' amine 5-Scheme-l may also be suphonylated to give the sulphonamide via methods that are known in the art such as treatment with a sulphonyl chloride, in the presence of an organic base, such as N-methylmorpholine, in an aprotic solvent such as dichloromethane.
Removal of the protecting group of 6-Scheme-l may be accomplished by treatment with a strong acid, such as anhydrous hydrochloric acid or triflouroacetic acid, in an anhydrous aprotic solvent, such as ethyl acetate or dichloromethane, to give 7-Scheme-l. The amine or amine salt of 7-Scheme-l may be acylated under standard conditions, such as EDC, HOBt and a carboxylic acid or with an acid chloride, to give amide derivatives 8-Scheme-l (n = 0, 1). The amine 7-Scheme-l may also be alkylated by treatment with an aldehyde in an aprotic solvent, such as dichloromethane, followed by reduction with sodium cyanoborohydride or sodium triacetoxyborohydride. Alternatively, the amine 7-Scheme-l may also be converted to the carbamate by treatment with a chloroformate in the presence of base, such as triethylamine or pyridine. The amine 7-Scheme-l may also be converted to the sulphonamide by treatment with a sulphonyl chloride in the presence of a base. The alcohol derivatives 8-Scheme-l may be oxidized to the ketone 9-Scheme-l under standard conditions such as chromium trioxide in acetic acid, in a solvent, such as acetone. These alcohols may also be oxidised with methylsulfoxide and oxalyl chloride in an aprotic solvent, such as dichlormethane at -78°C, followed by treatment with an organic base, such as triethylamine, and warming to room temperature. Altenatively, the alcohols may be oxidised with pyridine sulphur trioxide complex in methylsulphoxide with an organic base, such as triethylamine.
Scheme 2
I
I
I
I i
I 1 a) m-chloroperoxybenzoic acid, CH2CI2; b) NaN3, NH4CI, CH3OH:H2O (8:1); c) 1,3-propaned: TEA, CH3OH; d) RCO2H, EDC, HOBt, CH2CI2; e) pyridine sulphur trioxide complex, DMSO, Ί
Compounds of the formula (I) wherein n is 1, R^ and are amides and R is hydrogen may also be prepared as detailed in Scheme 2. Coupling of 1,2,3,6-tetrahydropyridine with a carboxylic acid in the presence of EDC and HOBT or with an acid chloride provides the amide 1-Scheme-2. Epoxidation of 1-Scheme-2 with m-chloroperoxybenzoic acid yields the epoxide 2-Scheme-2 which is opened with sodium azide in the presence of ammonium chloride to provide the azido alcohol 3-Scheme -2. The azide is then reduced under standard conditions which are known in the art, such as 1,3-propanedithiol with triethylamine, in a protic solvent, such as methanol, to provide the amino alcohol 4-Scheme-2. Coupling of the amine 4-Scheme-2 with a carboxylic acid in the presence of EDC and HOBT provides 5-Scheme-2 which is oxidised by methods which are known in the art, such as DMSO, oxalyl chloride and triethylamine at low temperature, to yield the ketone 6-Scheme-2.
Claims (1)
- Original document published without claims.
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Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6586466B2 (en) | 1995-10-30 | 2003-07-01 | Smithkline Beecham Corporation | Carbohydrazide-protease inhibitors |
AP9801222A0 (en) | 1995-10-30 | 1998-06-30 | Smithkline Beecham Corp | Proatease inhibitors. |
US6566373B2 (en) * | 1997-05-06 | 2003-05-20 | Smithkline Beecham Corporation | Protease inhibitors |
WO1998050534A1 (en) | 1997-05-08 | 1998-11-12 | Smithkline Beecham Corporation | Protease inhibitors |
KR20010082501A (en) | 1997-10-27 | 2001-08-30 | 개리 이. 프라이드만 | 4-Aminothiazole Derivatives, Their Preparation and Their Use as Inhibitors of Cyclin-dependent Kinases |
MA26618A1 (en) * | 1998-04-09 | 2004-12-20 | Smithkline Beecham Corp | PHARMACEUTICAL COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF MALARIA |
CO5180541A1 (en) * | 1998-12-23 | 2002-07-30 | Smithkline Beechman Corp | PROTEASE INHIBITORS OF THE 1,3-DIAMINOCETONE TYPE WITH 8-14 MEMBER RING |
EP1158986A4 (en) * | 1998-12-23 | 2002-03-27 | Smithkline Beecham Corp | Protease inhibitors |
AU2003261482B2 (en) * | 1998-12-23 | 2007-01-25 | Smithkline Beecham Corporation | Protease inhibitors |
US20030144175A1 (en) | 1998-12-23 | 2003-07-31 | Smithkline Beecham Corporation | Protease inhibitors |
EP1384713B1 (en) * | 1998-12-23 | 2008-10-15 | SmithKline Beecham Corporation | 4-amino-azepan-3-one derivatives as protease inhibitors |
TW200404789A (en) | 1999-03-15 | 2004-04-01 | Axys Pharm Inc | Novel compounds and compositions as protease inhibitors |
WO2001034599A1 (en) * | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
EP1231923A4 (en) * | 1999-11-10 | 2003-05-14 | Smithkline Beecham Corp | Protease inhibitors |
EP1233771A4 (en) * | 1999-11-10 | 2003-05-14 | Smithkline Beecham Corp | Protease inhibitors |
JP2003513928A (en) * | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | Protease inhibitor |
WO2001034565A2 (en) * | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
JP2003513972A (en) * | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | Protease inhibitor |
AU1474801A (en) | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
WO2001034153A1 (en) * | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
AU1474701A (en) * | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
EP1229912A4 (en) * | 1999-11-10 | 2003-05-07 | Smithkline Beecham Corp | Protease inhibitors |
SK13632002A3 (en) | 2000-03-21 | 2003-02-04 | Smithkline Beecham Corporation | C1-6-alkyl-4-amino-azepan-3-one compounds, process for the preparation thereof, pharmaceutical composition comprising the same and intermediates |
CO5280088A1 (en) * | 2000-04-18 | 2003-05-30 | Smithkline Beecham Corp | PROTEASA INHIBITORS |
NZ522965A (en) * | 2000-06-14 | 2004-06-25 | Smithkline Beecham Corp | Protease inhibitors |
EP1320370A4 (en) * | 2000-09-01 | 2008-10-22 | Smithkline Beecham Corp | Method of treatment |
MXPA03001982A (en) * | 2000-09-25 | 2004-05-14 | Actelion Pharmaceuticals Ltd | Substituted amino-aza-cycloalkanes useful against malaria. |
CA2433520A1 (en) | 2000-12-22 | 2002-07-04 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as cathepsin inhibitors |
US7030116B2 (en) | 2000-12-22 | 2006-04-18 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
US7132449B2 (en) | 2001-01-17 | 2006-11-07 | Amura Therapeutics Limited | Inhibitors of cruzipain and other cysteine proteases |
JP2004520365A (en) | 2001-01-17 | 2004-07-08 | アミュラ テラピューティクス リミテッド | Inhibitors of cruzipain and other cysteine proteases |
EP1362052B1 (en) | 2001-01-17 | 2007-03-07 | Amura Therapeutics Limited | Inhibitors of cruzipain and other cysteine proteases |
GEP20063741B (en) | 2001-02-23 | 2006-02-10 | Merck & Co Inc | Nonaryl-Heterocyclic NMDA/NR2B Antagonists |
US6538017B2 (en) | 2001-03-09 | 2003-03-25 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
US6710061B2 (en) | 2001-03-09 | 2004-03-23 | Ortho-Mcneil Pharamceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
WO2002080928A1 (en) | 2001-04-03 | 2002-10-17 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists |
EP1436255A1 (en) | 2001-09-14 | 2004-07-14 | Aventis Pharmaceuticals, Inc. | Novel compounds and compositions as cathepsin inhibitors |
KR20050044497A (en) | 2001-11-14 | 2005-05-12 | 아벤티스 파마슈티칼스 인크. | Oligopeptides and compositions containing them as cathepsin s inhibitors |
US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
KR100962972B1 (en) | 2002-07-26 | 2010-06-09 | 주식회사유한양행 | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
US7592360B2 (en) | 2003-06-04 | 2009-09-22 | Merck & Co., Inc. | 3-fluoro-piperidines as NMDA/NR2B antagonists |
US7378409B2 (en) | 2003-08-21 | 2008-05-27 | Bristol-Myers Squibb Company | Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity |
CN100368018C (en) * | 2005-05-26 | 2008-02-13 | 福建医科大学 | Fumor invasion and metastasis resisting function and use of venin cysteine proteinase inhibitor |
US7727978B2 (en) | 2006-08-24 | 2010-06-01 | Bristol-Myers Squibb Company | Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors |
US8119658B2 (en) | 2007-10-01 | 2012-02-21 | Bristol-Myers Squibb Company | Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors |
EP2240491B1 (en) | 2008-01-09 | 2015-07-15 | Amura Therapeutics Limited | TETRAHYDROFURO(2,3-b)PYRROL-3-ONE DERIVATIVES AS INHIBITORS OF CYSTEINE PROTEINASES |
KR20220115062A (en) | 2021-02-09 | 2022-08-17 | (주)오스티오뉴로젠 | Pharmaceutical Composition For Treating and Preventing Osteoporosis Comprising Compounds of Chromone Scaffold |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4994471A (en) * | 1989-05-12 | 1991-02-19 | Boc, Inc. | N-aryl-N-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
US5216168A (en) * | 1992-04-01 | 1993-06-01 | G. D. Searle & Co. | 2- and 3- amino and azido derivatives of 1,5-iminosugars |
US5374637A (en) * | 1989-03-22 | 1994-12-20 | Janssen Pharmaceutica N.V. | N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5057525A (en) * | 1981-10-01 | 1991-10-15 | Janssen Pharmaceutica N.V. | Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives |
US5206251A (en) * | 1992-04-01 | 1993-04-27 | G. D. Searle & Co. | 2- and 3- amino and azido derivatives of 1,5-iminosugars |
US5374623A (en) * | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
CA2111930A1 (en) * | 1992-12-25 | 1994-06-26 | Ryoichi Ando | Aminoketone derivatives |
US5585387A (en) * | 1994-10-07 | 1996-12-17 | Torcan Chemical Ltd. | Prepration of cisapride |
AP9801222A0 (en) * | 1995-10-30 | 1998-06-30 | Smithkline Beecham Corp | Proatease inhibitors. |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5374637A (en) * | 1989-03-22 | 1994-12-20 | Janssen Pharmaceutica N.V. | N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives |
US4994471A (en) * | 1989-05-12 | 1991-02-19 | Boc, Inc. | N-aryl-N-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
US5216168A (en) * | 1992-04-01 | 1993-06-01 | G. D. Searle & Co. | 2- and 3- amino and azido derivatives of 1,5-iminosugars |
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